Most GISTs express constitutively activated mutant isoforms of KIT. These are therapeutic targets for IM (Gleevec). The magnitude of clinical response of these tumors to IM shows marked heterogeneity. The investigators hypothesized that different mutant subtypes of KIT may confer differing susceptibilty to IM perhaps allowing tumor genotyping to predict response and prognosis in individual patients.

Multivariate analysis showed exon 11 mutation genotype to be the single best predictor of OR.

TTF was 576 days vs 308 vs 251 for those with exon 11mutation, exon 9 mutation and no mutation, respectively.

There was a trend toward improved OS for patients with exon 11 mutation vs other subtypes; p=0.04 but was not significant when adjusted for multiple comparisons.

Author's Conclusions

Activating KIT mutations are found in the majority of KIT+ GISTs.

The presence of exon 11 mutation correlates with the best clinical response to IM, as well as TTF and perhaps OS.

This study provides important evidence that gene expression profiling can be used to predict response to therapy and treatment outcome.

Clinical/Scientific Implications

In the new era of targeted cancer therapeutics, the rapidly increasing number of therapeutic options will make prediction of tumor response and prognosis important in determining choice of cancer therapy. This trial provides some of the best evidence currently available that therapies can be customized using gene expression profiling.

A similar trial in KIT+ GIST tested another KIT inhibitor, SU11248. In this trial, exon 9 mutants were seen to have a better response to therapy and better ultimate outcome. This further supports the continued use of gene profiling in chosing targeted therapies. Resistance mechanisms to IM, SU11248 and other similar compounds are being investigated. These mechanisms include KIT overexpression and further mutation. It may to useful to test these KIT inhibitor drugs in combination in order to combat these mechanisms of resistance. This research is currently underway in the pre-clinical stage